Gene therapy using Aβvariants for amyloid reduction

Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid O (AO) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length AO variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type AO in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of AO oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished AO levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of AO variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases.

Automated summary

Numerous aggregation inhibitors have been developed to block or reverse toxic amyloid formation in vivo, with recent studies focusing on short peptide inhibitors targeting different amyloidogenic regions. By creating a minigene to express full-length AO variants in the mouse brain, researchers have identified two variants that show promising therapeutic properties and used AAV delivery to express them in transgenic mice, leading to potential new strategies for Alzheimer's disease treatment, as well as a framework for developing tailored peptide inhibitors for other protein misfolding diseases.